I. INTRODUCTION

No discussion of
aging can be productive without a clear definition of what the communicator
means by “aging” and by other terms that are central to understanding in this
field.Failure to do so has, and still
is, creating enormous confusion, futility to effectively communicate, and
inability to grasp the fundamental differences between aging, the determination
of longevity, and age-associated diseases.

There is probably no
other scientific discipline in which there is such widespread lack of agreement
on what is meant by the most elemental words in the field.This failure to agree on the definitions of
basic vocabulary mirrors the present diffuse and chaotic state of the field
itself.The practitioners of what is
commonly called aging research, many of whom are aware of this problem, have
not yet become sufficiently motivated to rectify the situation.The problem is further compounded by the
ease with which neophytes can enter this field and become recognized as aging
researchers.

Because no experiment
can be done in the absence of a temporal variable, it is arguably true that all
biological research is research on aging.This common impression has attracted researchers to the field who have
no understanding of its fundamental concepts and even less understanding that
there is a lack of agreement by established practitioners on the definition of
common terms used.In order to avoid
these pitfalls and to attempt clear communication, I will define my terms
rigorously here and, in the process, not only reveal why misunderstandings of
fundamental concepts persist in this field but why longevity determination and
the diseases of old age can and are being modulated and why the fundamental
processes of aging cannot be modulated.

II. AGING AND LONGEVITY DETERMINATION

If our understanding of
the fundamental processes of aging biogerontology) is to advance, it will not
only be necessary to distinguish it from geriatric medicine (the
diseases and pathologies of old age) but it will also be necessary to
distinguish aging from the concept of longevity determination.The failure to make these distinctions has
contributed significantly to the frequent erroneous interpretation of research
data that is replete in this field.The
failure to make the distinction between aging and longevity
determination, is particularly pervasive by those who use invertebrate
models, where research data interpreted to bear on aging, in fact, should be
interpreted to bear upon our knowledge of longevity determination.Additional confusion frequently is added to
the mix when research findings that are applicable to the diseases of old age
are interpreted to advance our knowledge of the aging process.

III. AGING AND THE
DETERMINATION OF LONGEVITY

Aging can be defined as
a disorder that occurs at many levels of biological organization of which the
most fundamental is molecular. Although the disorder or changes that occur over
time at the atomic level generally are ignored by biogerontologists they are
the cornerstone of quantum mechanics.

Aging in living things
is a stochastic process that occurs after reproductive maturation and results
from increasing random, systemic, molecular disorder [1-3].It is no different in its fundamental aspect
of increasing loss of molecular fidelity from the aging phenomenon as it occurs
in the entire non-biological world.

The scientific
literature is replete with examples of age-related declines in protein
synthesis and degradation [4], loss of DNA fidelity [5], and effects with age
of oxidative stress on molecular fidelity [6]. Many of the chance events that
initiate this loss of molecular integrity and result in the subsequent aging
process have been extensively catalogued [7].

It is difficult not to be
impressed with what appears to be the fundamental inability of animals that
reach a fixed size in adulthood to maintain the fidelity of their molecules
after reproductive success.This
systemic increase in molecular disorder leads to the inescapable conclusion
that the sum of all these decrements is the etiology of the resulting age
changes that have been defined in other terms at higher levels of
organization.

We spend the first
twenty-five years or so of our lives producing, ordering, and replacing our
molecules with the greatest likelihood of absolute fidelity.Through natural selection, the fidelity of
anabolic processes is maintained by the efficiency of turnover and repair until
reproductive success or our species would vanish.Natural selection has favored energy states that differ for each
species because the molecules in each species need only to maintain their
fidelity long enough to guarantee reproductive success.The energy states that have been achieved at
the time of reproductive success will then indirectly govern subsequent
post-reproductive longevity.After
reproductive success, there is no species survival value in maintaining those
energy states indefinitely.Consequently, the random downward spiral of molecular disorder results
in changes at increasingly higher levels of organization in cells, tissues, and
organs, each of which reveals a catalogue of decrements that we label as age
changes.These events occur in spite of
the existence of well-known repair processes because repair processes
themselves are as vulnerable to the loss of molecular fidelity as are their
target molecules.Chance events that
create molecular disorder certainly occur during development but repair
mechanisms must overcome these or the species would vanish.However, after reproductive success the
balance of molecular disorder shifts to exceed the capacity for repair, and
thus the process of aging is initiated in those animals that reach a fixed size
in adulthood.

The random molecular
disorder and the diminished physiological capacity that molecular disorder
produces are the hallmarks of age changes.As the process accelerates the decrements in physiological capacity that
are produced increase vulnerability to predation, accidents, and the diseases
and pathologies of old age.

The proof that
individual survival beyond reproductive success is unnecessary for species
survival is clear.Humans have survived
with a life expectation of twenty-five years or less for 99.9 percent of the
several million years that we have been a species.No prehistoric human remains have been found to be older than
about 50 years.If the time in which
the human species has existed could be imagined on a twenty-four hour time
scale, aging as a process that most people in developed countries experience
would occur only a few seconds before midnight.

There is an almost
complete absence in the biogerontological literature of an appreciation that
the process of aging is identical, in principle, in both the animate and
inanimate worlds.That is, the random
loss of energy necessary to maintain molecular structure and function defines
the aging process in all matter.Furthermore, the processes by which inanimate objects are formed, with
or without human intervention, are analogous to the developmental processes
that occur in biological material.Thus, in both animate organisms and inanimate objects the elements of
design, materials used, and construction and repair processes all conspire to
influence the potential longevity of each.

Species survival depends
on a sufficient number of members living long enough to reproduce and, if
necessary, to raise progeny to independence.Natural selection favors animals that have greater survival
skills and, especially, redundant physiological reserve in vital organs beyond
the minimum needed to survive the damage that might be exacted by predators,
disease, accidents, or environmental extremes.Thus, selection for physiological capacity, beyond the minimum required
for life, increases the chances for animals to survive long enough to achieve
reproductive success just as redundant vital systems in complex machines,
better insures that they will reach their goals.The amount of excess physiological capacity, like the amount of
redundancy engineered into space vehicles, not only better insures that the essential
goal will be reached but, when it is reached, it indirectly provides the
potential for continued longevity beyond the primary goal [1-3, 8]. The level
of physiological capacity reached at the time of reproductive success in living
things is the determinant of their potential longevity. It is conceptually and
biologically different from the aging process.

Longevity determination
in living material is not a random process.It is governed by the amount of excess physiological capacity reached at
the time of sexual maturation that, through natural selection, was achieved to
better guarantee survival.Thus, the
determination of longevity is not directly determined by the genome but is only
indirectly determined.Longevity
can be thought of as a by-product, or as an incidental consequence, of the
primary purpose of genome activity -- to govern those events that take an
organism from conception to reproductive success.Aging, on the other hand, involves the loss of fidelity
that occurs in these pre-existing molecules, or their turnover replacements,
and can be thought of as the process that works against longevity
determination. Weakened members of a species will be culled by the forces of
natural selection because living long beyond reproductive success has
diminishing value for the survival of a species.Species survival is optimized when energy is spent to guaranty
reproductive success rather than spending it on increasing individual
longevity.

It is for this, and
other reasons, that biogerontologists are asking the wrong question: “Why do we
age?" The right question is: “Why do we live as long as we do?"

Longevity determination
in higher animals has been a profoundly neglected area of research.One class of animals that may provide some
answers to the determination of longevity are those animals that do not reach a
fixed size in adulthood and age slowly or not at all. If these animals do age,
the process is either negligible or it occurs below the limits of
detection.Representative animals of this
class include some tortoises, many sport and cold-water deep-sea fish, some
amphibians, and the American lobster.Even telomerase expression, the hallmark of immortal cells, has been
found at extraordinarily high levels in all the cells of negligibly aging
animals like the American lobster (Homarus americanus) and the rainbow
trout (Onchorhynchus mykiss)[9,10]. Whether these animals age at all,
and the reasons for this, have been almost entirely neglected.These animals are not immortal because, like
animals that do age, there is a constant threat of disease, predation, and
accidents [3, 11]. The time is long overdue for more intense study of the
phenomenon of negligible aging.

IV. GENES DO
NOT GOVERN AGING

Aging is not a
programmed process governed directly or entirely by genes [1-3].It is mostly those who work with
invertebrates who have interpreted their findings to involve genes in the aging
process.They have failed to appreciate
that the genes that they have identified are involved in longevity
determination and not in aging.

Genes are not involved
in aging because they have not been shown to affect, reverse, or arrest the
inexorable expression of molecular disorder that defines aging.Few, if any of the alleged aging studies on
invertebrates have employed an experimental design in which organisms having
the aging phenotype have been subjected to some variable that has been shown to
reverse or arrest that phenotype.Most
of the studies on invertebrates are more accurately interpreted to impact on
our understanding of longevity determination because the experimental results
have almost universally revealed an affect on physiological capacity or
developmental events that occur well before the aging process begins.The interpretation that gene manipulation
has resulted in a delay in the appearance of the aging process is more
accurately interpreted to be the result of increasing physiological redundancy,
improved repair processes, or the betterment of any other variable that results
in the greater likelihood that an animal will reach reproductive success.

Just as a
blueprint is vital to manufacture a complex machine and contains no information
to cause the aging of that machine, the genome is critical for biological
development but unnecessary to direct the aging of that animal.Both machine and animal eventually fail as a
result of increasingly irreparable loss of molecular fidelity, which in living
systems increases vulnerability to predation, accidents, or disease and in
inanimate objects increases vulnerability to analogous failures in some vital
component.

Another argument against
the direct role of genes in programming the aging process is that animals do
not age at the same rate, even when inbred, nor are the patterns of age changes
identical in each identical twin or other identical multiple births.When the random events characteristic of
aging are compared with the orderly, virtually lock-step, changes that occur
during genetically driven embryogenesis and development, that orderliness and
precision stands out in stark contrast to the quantitative and qualitative
disorder of age changes [3].The
variability in the manifestations of aging differs greatly from animal to
animal within a species but the variability in developmental changes differs
trivially.Humans from conception to
adulthood are virtually identical in respect to the timing of the stages
involved in biological development but from about thirty on, age changes
produce profound biological heterogeneity [3].

The faulty
interpretation that gene manipulation in invertebrates can arrest the aging
process has been extrapolated by authors in both the lay and scientific press
as potentially applicable to higher organisms including humans.This has resulted in the belief that in a
short time our increasingly better understanding of the genome and proteomics
will permit humans to modulate their own aging processes through gene
manipulation.This erroneous conclusion
has been reached simply because there has been a failure to appreciate the
critical distinction between the processes of longevity determination and
aging.Even if the determinants of
human longevity could be manipulated using genetic engineering, the results
have the potential to produce an enormous array of unintended consequences that
will be discussed subsequently.

V. AGING AND AGE-ASSOCIATED DISEASES

Aging is not a
disease.This distinction is central to
understanding why the resolution of the leading causes of death in old age --
cardiovascular disease, stroke, and cancer, will tell us little about the
fundamental biology of age changes.The
resolution of all three causes will only result in an increase of about fifteen
years in human life expectation [12].Then, aging, or the inexorable loss in physiological capacity that
underlies the cause of these pathologies will be revealed as the leading cause
of death.For the first time in human
history, most people will be found to die of old age.

The resolution of
age-associated diseases will advance our knowledge of the aging processes to
the same extent that the resolution of pediatric-associated diseases such as
poliomyelitis, acute lymphocytic leukemia, Wilms’ tumors, and iron deficiency
anemia increased our knowledge of childhood development. That is, no increase
occurred at all.

Aging is not a
disease because, unlike any disease, age changes

(1)occur in every animal that reaches a fixed size in adulthood;

(2)cross virtually every species barrier;

(3)occur in all animals that reach a fixed size in adulthood and only
after sexual maturation;

(4)occurin animals
removed from the wild and protected by humans, even when that species has not
been known to experience aging for thousands or even millions of years;

(5)increase vulnerability to death in 100 percent of the animals in
which it occurs; and

(6)occur in both animate and inanimate objects.

Today, the study of
age-associated diseases and the manipulation of biological development in lower
life forms dominate what is assumed to be the field of aging research.Neither research area will provide insights
into the aging process.One example of
this misunderstanding is that more than half the budget of the National Institute
on Aging in the United States is spent on Alzheimer’s Disease research, yet
motor vehicle accidents cause twice as many deaths [12] and from age 65 on,
Alzheimer’s Disease is not even one of the five leading causes of death [13].
The likelihood of dying from Alzheimer’s disease is 0.7 percent [12] and the
complete resolution of this disease will add about 19 days onto average life
expectation [12].Nor will that
accomplishment advance our knowledge of the fundamental biology of
aging.

In the minds of the
public, policy makers and many biomedical scientists, no one suffers or dies
from aging.We suffer and die from the
diseases associated with the aging process.Yet, age changes increase vulnerability to everything that is written on
the death certificates of the elderly.

No one over the age of,
say, 75 has or will die from what is written on his or her death
certificate.Death results from the
inevitable increase in systemic molecular disorder that living long enough
incurs.That disorder, when it occurs
in vital systems simply increases vulnerability to whatever was, or will be,
written on death certificates.

Because there are
multiple pathologies in older people the true cause of death is rarely
known.Because there are few autopsies,
and little research, the cause of most deaths in old age is still hidden in the
proverbial “black box.”The numbers of
autopsies that have been done on the elderly have continued to decrease in the
last few decades. In those rare instances where autopsies have been performed
on a large number of old people, the findings have shown that from 40 to 50
percent of the causes of death appearing on the death certificates have been
inaccurate [14 - 16]. In the most recent study of 93 postmortem examinations
done in an Israeli hospital over a twenty-year period, 42 percent of the causes
of death written on the death certificates were incorrect [17].Over this twenty-year period the rate of
autopsies dropped from 2.8 percent to 0.25 percent.These findings should raise considerable concern for the many
political, economic, actuarial, and scientific decisions that, without benefit
of autopsy, may have a forty-percent error rate.

More than 75 percent
of all human deaths in developed countries now occur in those over the age of
75.If the causes of these deaths are
resolved, we will not become immortal, but we will have revealed how death
occurs in the absence of disease.What
will be found is that the underlying cause of these deaths is the inexorable
loss of physiological capacity that results from increasing molecular disorder
in the cells of vital organs.This is
the hallmark of aging, and it will appear on all death certificates once the
present leading causes are resolved.

Both lay and science
policy makers, properly impressed with the future demographics of the graying
of all economically developed countries, are basing important policies and
decisions on a flawed understanding of what constitutes aging research and what
the results of that research might accomplish.Regrettably, most biomedical scientists also do not seem to understand
this fundamental distinction.The
evidence for this is clear.There is an
almost universal belief in biomedical research that borders on a mantra in
which it is stated that “the greatest risk factor for the leading causes of
death in humans is aging.”Yet,
inexplicably, the resources devoted to understanding the aging process are
microscopic compared to the resources devoted to the resolution of the leading
pathologies which all agree have their origins in the aging process.The present enormous imbalance in resources
available to study the fundamental aging process compared with the resources
available to study the derivative pathologies will continue until this
illogical reasoning becomes better appreciated.The greatest risk factor for all of the leading causes of death
will be better understood when we have an answer to the core question: “Why are
old cells more vulnerable to pathology than are young cells?”

Understanding how the molecules of an old
cell differ from those in a young cell and why those changes lead to pathology
has the potential to increase our understanding of the etiology of cancer,
cardiovascular disease, stroke, and even age-related accidents because the
etiology of all of these conditions are rooted in the differences.

VI.
AGING IS AN ARTIFACT OF CIVILIZATION

Aging is a phenomenon
unique to the human species because it is a consequence of implementing our
advancing knowledge of predator and accident avoidance, hygiene, and
biomedicine.Aging will also occur in
those animals that we choose to protect like our pet, zoo, and domestic animals
because we apply to those animals the same principles of hygiene, biomedicine,
and protection from accidents and predators that we have applied to ourselves.The resulting increase in the numbers of
older people in developed countries is, to a large extent, an unintended
consequence of these advances and an artifact of human civilization [1-3,
18].

Humans, and the
animals we choose to protect, are the only species in which large numbers experience
aging.Furthermore, old humans, or old
animals, are not essential for the survival of any species.The evidence for this is that humans have
had a life expectation at birth of thirty years or less for more than 99.9
percent of the time that we have inhabited this planet.The rarity or non-existence of old humans is
evident from the study of prehistoric human remains.None have revealed individuals older than about fifty years of
age.There appears to be no selective
advantage favoring the survival of old animals or old humans.

Members of exotic feral animal species, who for millions of years have
not experienced aging, reveal those changes when protected by humans as pets or
in zoos.It would be difficult to
explain how evolution could have selected for a process like aging that could
be made to appear in all members of a species after, perhaps, millions of years
of suppression. Because modern humans, unlike feral animals, have learned how
to escape death long after reproductive success, we have revealed a process
that, teleologically, was never intended for us to experience.One might conclude, therefore, that human
aging is an artifact unique to our civilization.

VII.
MODULATE WHAT?

It should be clear from
the preceding that intervening in the processes that influence the length of
human life depends on which of the three processes is to be considered --
aging, longevity determination, or the diseases of old age.

A. Modulating the Diseases of Old
Age

Clearly,
the elimination of or delay in the appearance of potentially fatal diseases can
and does increase the length of human life.That, plus efforts made to avoid accidents, are the approaches that have
yielded the greatest -- and the only -- effects on extending human
longevity.The evidence for how disease
elimination or reduction has influenced life expectancy is best illustrated by
realizing that it was the virtual elimination of acute infectious diseases that
resulted in the increase of about 27 years in life expectation that occurred in
developed countries within the last century [19].An
increase of that magnitude and within that period of time has not occurred in
any other century, nor is it probable that it will ever happen again.

21
of the 27-year increase in life expectation that occurred during the Twentieth
Century took place during the first 70 years. Only a six-year increase in life
expectation occurred in the following 27 years [19].For an increase of
even 10 more years in human life expectation to occur in the United States in
the next 50 years, mortality rates will have to decline to a level that has
never before been achieved [20].

In order to achieve
a life expectation greater than 100 it will be necessary to eliminate all
mortality risks from 1995 levels before age 85 [20]. The 1995 death rates would
have to decline by more than 50 percent at every age in order for life
expectancy to reach 85 years in the United States [20]. Even among Japanese
women who are the longest lived sub-group in the world, total mortality at
every age would have to drop 20 percent in order to raise life expectancy by
two years from its current 83 years. The mortality reductions at every age
required to achieve a 1-year increase in life expectancy at birth today are
more than twice those needed to achieve the same gain early in the 20th
Century [20]. It is not possible to reach life expectations of 100 or more
unless the method will not only completely eliminate all causes of death
currently appearing on death certificates but will also include an intervention
to slow or stop the fundamental aging process.Thus, the approximate 25-year increase in life expectancy that occurred
in the United States from [1900 - 2000] will be impossible to achieve in the 21st
Century, if ever.

It is abundantly clear
that the elimination of the present age associated chronic diseases, or slowing
the rate of their appearance, will indisputably increase the length of human
life.And, in fact, the number of years
of additional life that the elimination of each will produce has been
determined.Eliminating the major
cardiovascular disease as a cause of death will increase life expectancy at
birth in the U.S. by 6.73 years, eliminating stroke will produce an increase of
0.068 years; the resolution of cancer as a cause of death will result in an
increase of 3.36 years; while eliminating all accidents will result in an
increase of 0.92 years [12].The
elimination of all other causes of death will result in an increase in life
expectancy of about 4.26 years [12].Thus, although these numbers are not strictly additive (the resolution
of one cause of death will increase the number of years gained by the
resolution of the remaining causes of death) the elimination of all
causes of death currently written on death certificates will result in an
increase in life expectation of about fifteen years.

Significantly, the
United States Department of Health and Human Services and its subsidiary units
does not accept “aging,” “natural causes,” or “old age” as a valid cause of
death in its statistical summaries.Regardless of the precise number of years gained if all causes of death
currently written on death certificates are resolved, we will not become
immortal but we will succumb to the inexorable increase in molecular disorder
that defines the aging process.The
cause of death will then be universally attributable to the aging process and,
perhaps, more accurately described as loss of physiological function in some
vital organ.

All successful biomedical
research, and its implementation, results in adding time up to the fifteen-year
limit of what remains for extending human life expectation by intervening in
causes of death attributable to disease and accidents.In order to achieve life expectancies in
excess of fifteen years it will be necessary to modulate the aging process and
or the processes of longevity determination.

B. Modulating the Process of Aging

The eventual loss of
fidelity in most organic biological molecules is inevitable.In this respect even the dogma of the
immortality of the germ plasm is suspect.We know of no immortal organic biological molecules [21].The only biological property that is long
lasting on an evolutionary time scale is the information that is transmitted by
the genome but even that information is subject to mutation or change.Indeed, mutation is one of the few universal
properties of life.In addition to the
physical problem of intervening in a process in which energy states have been
disturbed in, perhaps, billions if not trillions of molecules, there are the
ethical and practical problems that would occur if it would become possible to
arrest, prevent, or reverse the aging process in humans. This issue will be
discussed subsequently.

Although biological
aging occurs in an open system, it is equivalent to an expression of the Second
Law of Thermodynamics or “increasing entropy.”Because aging is not a disease, the concept of seeking a remedy for it
is tantamount to seeking a remedy for embryogenesis of child or adult
development.Furthermore, there is the
complication that there exist thousands of manifestations of the aging process
that few would consider to be pathologies or diseases in need of a cure.Emergency Room personnel would not look
kindly on patients who seek admission because of complaints that their hair is
turning gray, wrinkled skin has just been observed, reaction time has
increased, short-term memory losses have been noted, or that the 25 year-old
Olympic champion sprinter arrived to say that he/she could no longer reach the
running speed that, at age 19, won the gold.

These examples are
representative of the hundreds of thousands of systemic losses in molecular
fidelity that lead to age changes and that are not pathologies in need of
treatment.But, when molecular disorder
occurs in cells or cell products that are part of vital systems and accumulate
sufficiently to increase vulnerability to pathology, a trip to the Emergency Room
may indeed become a necessity.

The inexorable loss in
molecular fidelity that defines aging can either lead to changes that may be an
affront to vanity, inconvenient, or simply uncomfortable.When the same kind of molecular mischief
occurs in the cells of vital organs and then leads to an increase in
vulnerability to disease or pathology, treatment is required because life may
become threatened.

Because of the
randomness of the underlying molecular process in which molecular fidelity
decreases, the rate of loss varies from cell to cell, tissue to tissue, and
organ to organ, making us what is analogous to a clock shop where there is
little probability that all clocks are measuring time identically.The difference in rates of cell aging
usually results in a few human tissues or organs containing the weakest links
and whose failure ultimately leads to death.This condition, in which the rates of biological deterioration differ
among tissues and result in only a few that contain the weakest link, is
analogous to what occurs in the aging process of the components of complex
inanimate objects like automobiles.

It is not difficult to
understand why an automobile of a particular make, model, and year of
manufacture will have a greater probability of failing because of a particular
weak link, like, for example, the electrical system.In another car of similar manufacture but different year or
model, the cooling or exhaust system will age fastest and become the most
probable system to fail first. There is inevitably a weakest link in the probability
of component failure in groups of similar complex entities.To engineers, the time when the weakest link
fails is called the Mean Time to Failure (MTTF).For a cheap car, it might be four or five
years and for United States citizens born today it is about 76 years.In developed countries, the weakest links in
humans are the vascular system and the cells in which cancer is most likely to
occur.The aging process increases
vulnerability in those cells that, in humans, are the weakest links and increase
vulnerability to the pathologies that we recognize as the leading causes of
death.

Biomolecules, like the
proteins that constitute most of our tissues, are extraordinarily complex
entities.The cause of the molecular
disorder that characterizes the aging process is the inevitable loss of energy
necessary to maintain the structural and functional integrity of virtually all
molecules that are synthesized during life.The fidelity of this vast array of biomolecules can last from pico
seconds to several thousand years after death in the case of some molecules
like DNA and millions of years in the case of bone.

The likelihood that
human intervention in the aging process might be possible is presently thought
by many to be restricted to manipulating the only process known to do so in
lower animals.Yet, even that process
is subject to the fog of interpretation.The process is Caloric Restriction (CR).Although demonstrated in many species, including its likely
occurrence in non-human primates, it has yet to be demonstrated to occur in
humans [22].

Even if it is applicable
to humans, there is an alternative interpretation of the commonly accepted
dogma that CR modulates the aging process or the determination of
longevity.That alternative is based on
the fact that most of the dietary-restricted animal experiments use control
animals that are fed ad libitum or some arbitrary reduction of this
quantity; what may have been discovered is not that restricted animals live
longer but that their longevity more closely resembles that of feral
animals.Thus, what might have been
discovered is not that caloric restriction increases longevity but that
overfeeding is life shortening.One is
led to conclude that calorie restricted animals are a more accurate representation
of the length of life of feral animals.

We do not know what the
usual caloric intake is of feral animals whose laboratory counterparts are
being studied.Thus, any assumption
about what constitutes a proper control is suspect.Consequently, what are thought to have been the experimental
animals in Calorie Restriction studies become the controls and what are thought
to have been the controls become the experimental animals.Indeed, there is preliminary evidence that
captive feral rodents placed on a calorie-restricted diet do not show an
increase in mean longevity.However, it
was found that the longest lived animals (about 10 percent) were calorie
restricted [S. Austed, Personal Communication].

Even if we assume that
caloric restriction will increase the length of human life, a near starvation
diet is unlikely to be acceptable to most people whose quality of life is more
important than is their quantity of life.The evidence for this is that the phenomenon of caloric restriction has
been known for almost 75 years, yet very few people have practiced it.Furthermore, no practitioner of caloric
restriction has been found to have a life expectation that exceeds values found
for the general population.

The only known way that
the aging process can be circumvented in inanimate objects is by the
replacement of old parts with new.Although parts replacement is possible in organisms including humans,
the only certainty is that replacing old organs with young organs increases
life expectancy. This result is no
different from the many other medical, hygienic, and safety procedures that
have been implemented to avoid or postpone death. None treat the fundamental
process of aging. Furthermore, the replacement of one’s brain with that of
another, even if possible, would result in the loss of self-identity, thus
defeating the purpose of extending life.Some computer futurists have claimed that circumventing the aging
process might some day be done by uploading the contents of a brain to a
storage device and then downloading the contents to a young brain that has been
erased.However, no consideration has
been given to the complaint that might be expressed by the owner of the younger
brain, the contents of which are about to be deleted.Nevertheless, these kinds of thought experiments that involve
parts replacement all result in the same dilemma:The original identity of any object -- animate or inanimate --
will be lost as we approach or even succeed in the complete replacement of all
of its parts. Thus, full replacement of all parts results in a different
object.

In summary, there is
little likelihood that the fundamental aging process will ever be capable of
modulation by human intervention.Our
present ignorance of the process is so great and the resources available for
its study so small that the likelihood of an intervention is, in my view, close
to zero.Our knowledge of the multiple
trillions of molecules that might be involved in the process and how they might
be replaced or repaired is too primitive to expect that we will have the
ability to intervene in the foreseeable future.In fact, intervention may border on the impossible because the
aging process is fundamental to all matter, living or dead.Finally, modulating the aging process also
has an enormous array of unintended consequences that will be discussed
subsequently.

C. Modulating Longevity
Determination

The likelihood of
reversing or slowing the determinants of longevity are at least as daunting as
would be attempts to modulate the aging process.The determinants of longevity are dependent on the physical and
chemical state of molecules reached at the time of sexual maturation and that
provide all of the physiological capacity that exists at that age.Thus, any effort to modulate the process at
later ages would depend upon restoring molecules in an older individual that
could be identified as “old” to their former youthful state.As with the aging phenomenon, the complexity
of intervening in the determination of longevity is further compounded by the
probability that the molecular changes that occur may not only be qualitative
but also quantitative.

In spite of the
monumental difficulties of modulating longevity determination in an aged
organism, it has been achieved by the manipulation of genes very early in the
developmental stages of some invertebrates (for examples, see [23, 24]).This kind of gene manipulation, even if it
was possible to do in humans, is unlikely to be practiced, if for no other
reason than because of the insurmountable ethical considerations.

Notwithstanding
these considerations, it is likely that a natural increase in the human
lifespan is presently occurring; but it is occurring on an evolutionary time
scale and thus so slowly that our ability to detect it could only be made after
millennia of careful record keeping.This belief is based on persuasive evidence in the fossil record that
suggests that the life spans of most animal species increase as evolution
proceeds [1].

VIII.
UNINTENDED CONSEQUENCES OF MODULATING HUMAN LONGEVITY

Although it is
indisputable that human intervention in slowing or eliminating the diseases of
old age has occurred with a resulting increase in longevity, there is no
evidence that humans have ever developed an intervention that has perturbed
either the processes of aging or longevity determination [25]. And, the
likelihood that it will ever become feasible to perturb either process is, as
indicated previously remote, if not impossible.

Other than the
biological considerations of why perturbing either process in humans is
unlikely, one must also consider in the abstract what the consequences might be
of having that power.The desire to
intervene probably originated when prehistoric humans first recognized the phenomenon
of aging as undesirable and therefore requiring treatment. The idea has
remained unchanged to this day and has given to aging its negative connotation
of deterioration, approaching pathology, pain, and death.

Yet, the hundreds of
thousands of septuagenarians who follow the sun in their recreational vehicles,
no longer have child-rearing responsibilities, possess good health and a modest
income will disagree.To them, and
others who believe that their intellectual growth doesn't stop, and that the
carefree seventies and beyond are the best time of their lives, arresting adult
development at an earlier age would be unthinkable.

There is the greater
likelihood that it is not the fear of aging but fear of the pathology and pain
that precedes approaching death that motivates those who believe that having
the power to extend human longevity is desirable. The term
"prolongevists" first coined to describe the "… significant
extension of the length of life by human intervention..." has precedent
over the illogical term "anti-aging" and its 3,500 year-long history
has been well described in the monumental work by Gruman [26].

Prolongevists assume
that intervening in the aging process is not only possible but also
desirable.Neither is likely.Advocates differ in their beliefs in respect
to whether intervention means stopping, slowing, or reversing the process.Stopping, or reversing the process defies
fundamental laws of physics and chemistry, and slowing the process is rife with
unintended negative consequences.If
advocates of intervention would define aging properly and distinguish it from
its associated diseases and the process of longevity determination then the
folly of intervention should become apparent.

To know what the future
societal impact might be of even a fifteen-year increase in life expectation
(which is what would occur if all causes of death currently written on death
certificates were to be eliminated), one might consider the changes that have
occurred from 1931 until the present. During these 70 years an approximate
fifteen-year increase in life expectation has occurred [12]. Of the many
comments that might be made, three observations are as follows: (1) the
increase in the number and proportion of older people; (2) the greater time spent
in frailty and dependency in old age; and (3) the political and economic
consequences that both of these have had [12].

In an exercise intended
to explore what would occur if tampering with the aging process becomes
possible, one might imagine the simplest method: a pill that slows the aging
process.The first concern is that
those involved in the discovery and the rich and powerful will have earliest,
or depending on availability, even the only, access. It is questionable whether
these would be the most important to be favored first, or at all.Presumably, the pill would also become
available to the antisocial killers, tyrants, and those guilty of genocide
along with those who contribute to or benefit human civilization.

Of the many predicaments
that could be imagined, one is “When in life would one choose to take the
pill?”Before making the decision to
administer it in youth, one should be aware of the fact that virtually any age
might be chosen and with good reason.

Furthermore, at what age
would one choose to have their aging process slowed if they had not yet passed
through most ages in order to make an informed decision?Of course, once having passed through the
desired age, how then would one reverse time to that earlier and better age? It is also the stuff of science fiction to
expect that all of ones fellow humans and the environmental conditions that
contributed to that better earlier age would have remained unchanged.And, switching the effects of the pill on or
off seems even less realistic.Of the
many other bizarre scenarios that could be imagined, it would not be surprising
to find families in which children who chose not to take the pill might find
themselves biologically older than their parents, who did.Finally, slowing aging is not likely to be
an appealing option for a substantial part of the worlds population who find
themselves, poor, oppressed, sick, or all three.

We interact with each
other to a substantial extent as a function of our perceptions of relative age.
The destruction of that relationship would have enormous negative personal and
societal consequences.

One might well argue
that when it is demonstrated that aging can be stopped, slowed, or reversed in
a far less complex entity as one's automobile then attempting it in humans
might be taken more seriously.The goal
of slowing the aging process also might be viewed in the same light that we
view slowing developmental processes.Slow physical or mental development in childhood is viewed universally
as a serious pathology.If retarding
the mental and physical development of someone from birth to age twenty years,
for ten years, in order to gain a decade of additional life, is unattractive
then slowing one’s aging processes in later life also will not be attractive
and for the same reasons.The
probability that either physical or mental development could be slowed
independent of the other borders on science fiction.

Yesterdays'
prolongevists who searched for the Fountain of Youth, advocated sleeping with
young virgins, encouraged monkey testicular grafting, and ate yogurt, simply
have been replaced with their modern equivalents and with an equal probability
for success.The touting of
interventions capable of slowing the aging process will not end because there
is too much quick profit to be made by those who have discovered how rich one
can get by exploiting the ignorance and gullibility of the public.

As some civilizations
have, our society must learn that the phenotype of aging should be valued just
as much as is the phenotype of youth.Then the misplaced passion for cosmetic surgery, anti-aging nostrums,
and similar snake-oil remedies to arrest aging will be recognized for what they
truly are -- at best a cover-up for an irreversible and inexorable process and
at worst a delusion and waste of money for the uninformed.

If the main goal of our
biomedical research enterprise is to resolve causes of death then every old
person present today becomes a testimony to our past successes.Biogerontologists have an obligation to
emphasize that the goal of research on aging is not to increase human longevity
regardless of the consequences but to increase longevity free from functional
disability and dependence.

Perhaps the least
imperfect goal for which biogerontologists, geriatricians and other biomedical
scientists should seek is to resolve all of the conditions that compromise good
health regardless of age.By reaching
this goal, we will reveal that all subsequent [24] deaths are caused by
decrements in physiological capacity, - the hallmark of aging.The goal then should be for all humans to
die of something that they have not previously died of before -- old
age.

This, in fact, is
precisely the goal that the biomedical research establishment –unwittingly --
has set for itself, because virtually all such research is directed toward the
resolution of physical or mental disorders.The resources available to study the underlying aging and
longevity-determination processes presently are insignificant.

REFERENCES:

1. Hayflick, L (1996). How and Why We
Age. New York: Ballantine Books.

5. Vijg, J and Dolle,
MET (2001) Instability of the nuclear genome and the role of DNA repair In:
Masoro EJ and Austed SN, Handbook of the Biology of Aging. pp. 84-113:
Academic Press, San Diego, California.